This invention relates to new spiro-linked cyclic imido derivatives having the property of inhibiting the enzyme aldose reductase in vivo, their base addition salts and processes for their manufacture.
In the present market of pharmaceuticals, such antidiabetic agents as sulfonyl ureas are only used for symptomatic treatment against hyperglycemia, but little effective for reduction of prevention of diabetic complications.
It has been shown that aldose reductase was involved in diabetic complications such as diabetic cataracts, neuropathy and retinopathy (J. H. Kinoshita et al., JAMA, 246, 257, -81). Enzyme aldose reductase catalyzes the reduction of aldoses such as glucose and galactose to form polyols such as sorbitol and galactitol. These polyols penetrate cell membranes poorly and, once formed, tend to be removed only by further metabolism so that net effect is an accumulation of them inside the cell. In such hyperglycemia as diabetes mellitus, the higher sugar level activates aldose reductase to accelerate the further conversion of glucose to sorbitol. As a consequence, sorbitol accumulates abnormally within the cell, for example in the lens, peripheral nerve, kindney and vascular tissues, causing a rise in internal osmotic pressure and creating a hypertonic condition which may be in turn sufficient to destroy or impair the function of the cell themselves. Therefore, it may be of therapeutic value for controlling certain chronic diabetic complications by depressing of polyols responsible for systematic dysfunctions. That is to say, function in system may be able to maintain normally by inhibiting aldose reductase activity and followed by preventing the abnormal accumulation of olyols.